The long-term career goal of the candidate is to become an independent translational and clinical investigator specializing in the development of innovative immune-based therapies for malignancy. The candidate will gain the necessary skills and training through a multifaceted career development plan that includes didactic instruction through the completion of a Master's Degree in an NIH K30-funded Clinical Research Curriculum, and the completion of two related clinical trials at the University of Minnesota NCI- designated Comprehensive Cancer Center. Enhanced understanding about the role of the innate immune system in tumor surveillance has inspired interest in the development of cancer immunotherapy based on innate immune activation. An explosion of research has focused on Toll-like receptors (TLR), a class of pattern recognition receptors expressed on the cells of the innate immune system that recognize conserved molecular features of pathogens. TLR ligation triggers dendritic cell maturation and activation of the innate and adaptive immune responses. Synthetic small molecule TLR agonists have been effective in treating some malignancies, and evidence suggests that at least part of the efficacy is mediated through the indirect activation of natural killer cells. Increased appreciation for the role of killer immunoglobulin-like receptors (KIR) in mediating NK cell alloreactivity against tumors has opened another avenue for manipulation of innate immunity to treat cancer. The immediate scientific objective of this application is to study the anti- tumor activities of NK cells in 2 Phase II trials. Specific Aim 1 involves of haploidentical NK cell therapy to treat metastatic breast cancer, and Specific Aim 2 will test the efficacy of a TLR7 agonist against chronic lymphocytic leukemia. In addition to assessing clinical efficacy, the sub-aims of this proposal describe laboratory-based experiments to understand the mechanisms of the treatments. The candidate will work towards a long-term scientific objective of developing multifaceted anti-tumor treatments which effectively combine different immune and non-immune therapies in complementary or synergistic manners. This research will advance the field of anti-cancer immunotherapy by providing information about two novel treatment strategies and new insights into the mechanisms by which the innate immune system interacts with tumors. This training will position the candidate to become an independent, funded clinical investigator.